Abstract
Liver X receptors (LXRs) play a pivotal role in fatty acid (FA) metabolism. So far, the lipogenic consequences of in vivo LXR activation, as characterized by a major hepatic steatosis, has constituted a limitation to the clinical development of pharmacological LXR agonists. However, recent studies provided a different perspective. Beyond the quantitative accumulation of FA, it appears that LXRs induce qualitative changes in the FA profile and in the distribution of FAs among cellular lipid species. Thus, LXRs activate the production of polyunsaturated fatty acids (PUFAs) and their distribution into phospholipids via the control of FA desaturases, FA elongases, lysophosphatidylcholine acyltransferase (LPCAT3), and phospholipid transfer protein (PLTP). Therefore, LXRs control, in a dynamic manner, the PUFA composition and the physicochemical properties of cell membranes as well as the release of PUFA-derived lipid mediators. Recent studies suggest that modulation of PUFA and phospholipid metabolism by LXRs are involved in the control of lipogenesis and lipoprotein secretion by the liver. In myeloid cells, the interplay between LXR and PUFA metabolism affects the inflammatory response. Revisiting the complex role of LXRs in FA metabolism may open new opportunities for the development of LXR modulators in the field of cardiometabolic diseases.
Highlights
Beside their prominent role in controlling cholesterol homeostasis, regulation of fatty acid (FA) metabolism appears to be an important function of liver X receptors (LXRs), and pivotal studies have highlighted major lipogenic activity of LXRs [1,2,3]
In vivo stimulation of LXR activity by synthetic agonists such as T0901317 induces a dramatic activation of FA and triglyceride synthesis in the liver in different mouse models resulting in hepatic steatosis, stimulation of VLDL secretion, and increased plasma triglyceride levels [1,9,10,11]
It was demonstrated that the activation of LXRs by synthetic agonists induced, in a coordinated manner, the expression of all the enzymes required for polyunsaturated fatty acids (PUFAs) synthesis, including activation (ACSL3), delta 6 and delta 5 desaturation (FADS2 and FADS1), and FA elongation (ELOVL5) [17]
Summary
Beside their prominent role in controlling cholesterol homeostasis, regulation of fatty acid (FA) metabolism appears to be an important function of liver X receptors (LXRs), and pivotal studies have highlighted major lipogenic activity of LXRs [1,2,3]. LXRs mainly induce the synthesis of monounsaturated fatty acid, notably oleic acid (C18:1 n-9) and palmitoleic acid (C16:1 n-7) due to the coordinated induction of FASN and SCDs [11] These FAs are subsequently incorporated in triglycerides and phospholipids. By controlling the synthesis of biologically active PUFAs as well as their distribution into cellular glycerophospholipids, LXRs could be able to modulate the biological properties of cell membranes and the release of PUFA-derived mediators In accordance with this hypothesis, recent works have identified several biological functions of LXRs that are directly mediated by modulation of PUFA and phospholipid metabolism
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
